Radiation is a primary modality in cancer treatment. Radiation can also reduce tumor growth outside the treatment field, often referred to as the abscopal effect. The mechanisms and therapeutic potential of the abscopal effect have not been fully elucidated. Here, we evaluated the role of vaccination directed against a tumor-associated antigen (TAA) in the induction and amplification of radiation induced abscopal effects. Active-specific immunotherapy with a TAA- specific vaccine regimen was used to induce and potentiate T-cell responses against carcinoembryonic antigen (CEA) in combination with local radiation of subcutaneous tumors. We examined the potential synergy of a poxvirus-based CEA vaccine regimen in CEA-transgenic (Tg) mice in combination with either external beam radiation or brachytherapy of local tumors. The induction of CD8+ T-cells specific for multiple TAAs not encoded by the vaccine were observed after the combination therapy. In two tumor models, the antigen cascade responses induced by vaccine and local radiation mediated the regression of antigen negative metastases at distal subcutaneous or pulmonary sites. Clinically, local control of the primary tumor is necessary and can sometimes prevent metastases, radiation generally fails to control pre-existing metastases. By The studies here suggest that by coupling tumor radiation with immunotherapy, the abscopal effect can transcend from anecdotal observation to a defined mechanism that can be exploited for the treatment of systemic disease. As our understanding of the immunomodulatory effects of radiation has improved, interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation, culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further, more robust immune system activation. We have now focused preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy, including external beam radiation, radiolabeled monoclonal antibodies, bone-seeking radionuclides, and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly, we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination.